Epithelial–mesenchymal transdifferentiation of renal tubular epithelial cells induced by urinary proteins requires the activation of PKC-α and βI isozymes

Abstract

Proteinuria is a common feature for almost all glomerular diseases and reflects the severity of the glomerular lesion. The presence of a large amount of proteins in tubular fluid, however, may also contribute to the development of RIF (renal interstitial fibrosis). Endocytosis of albumin in proximal tubular cells triggers PKC (protein kinase C)-dependent generation of reactive oxygen species and secretion of chemokines. As a family including 12 isozymes, which PKC isozymes participate in RIF is still unclear. EMT (epithelial-mesenchymal transdifferentiation) of RTECs (renal tubular epithelial cells) plays a crucial role in the progress of RIF induced by proteinuria. In the present study, we investigated the role of classical PKC isozymes in the proteinuria-induced EMT of RTECs. Employing immunochemical staining, we found that PKC-α, -βI and -βII were expressed in glomerulus and in RTECs in both normal and diseased renal tissues, while PKC-γ was only expressed in podocytes in the glomerulus. Treatment of HK-2 cells with extracted urinary proteins resulted in EMT, as evidenced by morphological changes, decreased E-cadherin expression, increased α-SMA (α-smooth muscle actin) expression, as well as production of type I collagen and fibronectin. Western blot analysis of PKC isozymes in the cytosolic compared with membrane fraction revealed translocation of PKC-α and -βI, but not PKC-βII, in HK-2 cells undergoing EMT. Pretreatment with selective PKC-α inhibitor G-6976 or PKC-β inhibitor significantly attenuated EMT induced by urinary proteins. In summary, the present study suggested that PKC-α and -βI play critical roles in the EMT of RTECs in response to urinary proteins.

Obstructive Sleep Apnea and Kidney Disease: A Potential Bidirectional Relationship?

“…Renal hypoxia induces epithelialmesenchymal trans-differentiation of the tubular cells and activates fibroblasts, which in turn plays a crucial role in the progression of renal interstitial fibrosis and damage of peritubular capillaries. 82,83 Trans-differentiated cells also stimulate the production of collagen I and α-smooth muscle actin. 79 As a result, tubular atrophy occurs and further impairment of oxygen supply is induced.…”

Association of PAX2 with Cell Apoptosis in Unilateral Ureteral Obstruction Rats

“…RTEC suffering from EMT plays a crucial role in the progression of RIF. 16,17 α-Smooth muscle actin (α-SMA), as a specific marker for EMT, takes part in the development and progression of RIF. 16,18 Of all the cytokines and growth factors involved, transforming growth factor (TGF)-β1 plays the most important role, and the increased expression of TGF-β1 is closely correlated with the development of RIF.…”

“…16,17 α-Smooth muscle actin (α-SMA), as a specific marker for EMT, takes part in the development and progression of RIF. 16,18 Of all the cytokines and growth factors involved, transforming growth factor (TGF)-β1 plays the most important role, and the increased expression of TGF-β1 is closely correlated with the development of RIF. 19,20 TGF-β1 is known to be one of the major mediators which leads to RIF by inducing the production of α-SMA and ECM (Col-IV and FN) in the renal interstitium.…”

Knocking down TCF8 inhibits high glucose- and angiotensin II-induced epithelial to mesenchymal transition in podocytes

“…Previous studies reported that a high concentration of glucose and angiotensin II may promote EMT in kidney epithelial cells (16,17). The current study examined whether those substances would have the same effect on podocytes.…”